Synthesis and Application Dichalcogenides as Radical Reagents with Photochemical Technology

Dichalcogenides (disulfides and diselenides), as reactants for organic transformations, are important and widely used because of their potential to react with nucleophiles, electrophilic reagents, and radical precursors. In recent years, in combination with photochemical technology, the application of dichalcogenides as stable radical reagents has opened up a new route to the synthesis of various sulfur- and selenium-containing compounds. In this paper, synthetic strategies for disulfides and diselenides and their applications with photochemical technology are reviewed: (i) Cyclization of dichalcogenides with alkenes and alkynes; (ii) direct selenylation/sulfuration of C−H/C−C/C−N bonds; (iii) visible-light-enabled seleno- and sulfur-bifunctionalization of alkenes/alkynes; and (iv) Direct construction of the C(sp)–S bond. In addition, the scopes, limitations, and mechanisms of some reactions are also described.


Introduction
Organosulfur and organoselenium compounds play an increasingly important role in organic synthesis and material science as well as in pharmaceutical applications [1]. In particular, C-S bonds exist in numerous natural products and biological and pharmaceutical compounds, such as nelfinavir, esomeprazole, and cephalosporin-type antibiotics, most of which have demonstrated antibacterial, antiviral, antitumor, and anti-inflammatory activities [2]. Furthermore, various organoselenium compounds have been identified as therapeutic agents, with anticancer, antiviral, and anti-Alzheimer's properties [3]. They have also been explored as fluorescent probes, catalysts in organic synthesis, and functional organic materials [4]. Thus, the efficient construction of C-S and C-Se bonds has generated considerable interest in organic synthesis in the past decades.
The disulfide bond is an important functional group, existing in a large number of chemical and biological molecules, such as oxidized glutathione (GSSG), some proteins (thrombospondin-1 and protein disulfide isomerase [PDI]), and even some natural drugs (mitomycin disulfides and leinamycin). Disulfide bonds play a vital role in organisms and are generally obtained by covalently crosslinking two cysteine residues. GSSG and reduced glutathione (GSH) can maintain a balance of oxidation and reduction in cells, while disulfide bonds predominantly maintain the stability of protein conformation to ensure biological activity [5]. Compared with sulfur, Se has a larger diameter and a weaker negative charge [6]. The diselenide bond (Se-Se) is more redox active than the S-S bond in the microenvironment of cancer cells because its bond energy is lower than that of the disulfide bond (Se -Se = 172 kJ/mol; S -S = 268 kJ/mol) [7]. In addition, Sun et al. [8] studied the bond angles of sulfur bonds and selenium bonds and found that S-S (94.6 • /97.9 • ) and Se-Se (89.9 • /93.3 • ) had bond angles closest to 90 • . In comparison, the diselenide bond has sufficient structural flexibility to establish the most favorable conformation during self-assembly.  [11] discovered that diselenides can be prepared rapidly and in large quantities by using H2O2 or the corresponding selenic acid as the oxidant. Recently, Chinese scholars have found that diselenides can also be efficiently prepared using trichlorocyanuric acid [12].
Selenium transfer reagent method ( Figure 1c): In 1995, Zhou et al. [13] first reported the use of a selenium transfer reagent to synthesize diselenide. Under mild conditions, the reaction of selenoamides with various alkyl halogenated hydrocarbons can produce alkyl diselenides in high yields. The disadvantage of this method is that selenoamides are not easy to prepare.
Catalytic cross-coupling method ( Figure 1d): In 2010, Oscai's group [14] first reported the preparation of diselenide compounds via cross-coupling catalyzed by copper oxide nanoparticles. Compared with traditional methods, nanocatalysts have been effectively processed, with their high surface area and special morphology, making them effective as catalysts in organic synthesis. This method is applicable not only to the preparation of alkyl and aryl diselenides but also to heterocyclic diselenides, with high universality and generally high yields.
Copper-catalyzed one-pot method ( Figure 1e): In 2013, Zhang et al. [15] developed a method using cuprous chloride as the catalyst, acetylacetone as a ligand, and an aromatic halide as the raw material, which was directly reacted with selenium to synthesize diaryl selenide compounds.
Sulfur reagent transfer method ( Figure 1f): In 2003, Kaushik et al. [16] also reported a new and effective sulfur transfer reagent (C6H5CH2N(Et)3)6-Mo7S24) to react with halogenated hydrocarbons to obtain disulfides. The reaction conditions are mild, and the yield is satisfactory.  [16] also reported a new and effective sulfur transfer reagent (C 6 H 5 CH 2 N(Et) 3 ) 6 -Mo 7 S 24 ) to react with halogenated hydrocarbons to obtain disulfides. The reaction conditions are mild, and the yield is satisfactory.
Oxidative coupling method ( Figure 1g): In 2005, Joshaghani [17] reported a new method for the mass production of disulfides. This method uses tert-Butyl hydroperoxide (TBHP) as an oxidant to directly transform thiols to disulfides, which is fast and efficient.
Microwave irradiation method ( Figure 1h): In 2007, Lenardao's group [18] discovered that symmetric disulfides were rapidly synthesized from mercaptans under solvent-free conditions using a solid Al 2 O 3 /KF system as a catalyst under microwave irradiation at room temperature. This improved method is generally aimed at the conversion of liquid mercaptans to disulfides, and the yields range from moderate to good. In addition, the catalyst system could be used twice without any decrease in activity.
Reductive coupling method ( Figure 1i): In 2009, Yao [19] reported that triphenylphosphine was used for the reductive coupling of benzenesulfonyl chloride at room temperature to easily obtain disulfides.
Nanocatalysis method (Figure 1j): In 2013, Saidi [20] found that using nano iron oxide as a catalyst and hydrogen peroxide as an oxidant at room temperature can efficiently oxidize mercaptan to disulfide ether. Nano iron oxide is an efficient and recyclable catalyst, and hydrogen peroxide is a green oxidant. The advantage of this method is that the catalyst is stable and reliable, the reaction conditions are mild, and the selectivity is high.
Oxidation of thiols ( Figure 1k): In 2015, Noël et al. [21] used eosin Y dye to oxidize thiols to disulfide derivatives under visible light. Compared with heavy metal catalysts, using organic dyes as photosensitizers is less toxic and less expensive. This method is suitable for aliphatic thiols, aromatic thiols, and heterocyclic thiols, with yields ranging from 86% to 99%. The advantage of this method is that the reaction time can be reduced from hours to minutes. Moreover, drugs such as oxytocin and disulfiram can be synthesized using this method.
Conversion from Na 2 S 2 ( Figure 1l): This method is used to prepare symmetrical disulfide derivatives by the reaction of alkyl bromide with Na 2 S 2 . In 2017, Wang and colleagues [22] reported a method for the synthesis of symmetric disulfides. This method uses a bromine-containing dienamine reacted with Na 2 S 2 to afford the corresponding symmetrical disulfides in 54% yield.
Recently, Chen's group [23] reported a class of N-acyl hypersulfonamides containing S-N bonds based on copper-catalyzed amination of azobene-mediated thiols. This class of S-N compounds was shown to be a good thiol sulfide reagent for the preparation of various disulfides (Figure 1m).

Cyclization of Diselenides with Alkenes and Alkynes
The ingenious design of novel radical addition cyclizations has emerged as an increasingly powerful tactic to construct complex molecules in an atom-and step-economical manner. Over the past decade, visible-light-driven photoredox catalysis has stimulated a resurgence of interest in the exploration of radical reactions.
In 2013, Ragains and coworkers reported a visible-light-promoted selenocyclization of alkenes at room temperature (Scheme 1) [24]. In this reaction, bench-stable PhSeSePh was combined with CBr 4 under the irradiation of a 5W blue light-emitting diode (LED), resulting in the in situ generation of reactive PhSeBr. This reaction showed a broad substrate scope, generating O-heterocycles in high yields along with N-heterocycles in moderate to high yields. Notably, in CH 2 Cl 2 as a solvent, diphenyl ditelluride provided successful tellurofunctionalization products in 53-75% yields. To further demonstrate the application of this method, the amaryllidaceae alkaloid, γ-lycorane, was synthesized. Free radical validation experiment and density functional theory (DFT) calculation suggested visiblelight irradiation promoted the phenylselenyl radical abstraction of bromine from CBr 4 to generate phenylselenyl bromide in situ. The detailed mechanism of these reactions is still under investigation. In 2017, an efficient photocatalyst-free approach for the preparation of selenium-substituted spiro [4,5] trienones based on visible-light-induced selenium radical cyclization of N-aryl alkynamides was described by Baidya and coworkers (Scheme 2) [25]. Diverse N-aryl alkynamides and diaryl diselenides bearing electron-donating as well as electronwithdrawing groups in an aryl ring achieved the products under an oxygen atmosphere at room temperature. In addition, good yields were achieved in gram-scale reactions. A spiro-ring-opening strategy was realized to give fully substituted acryl amides 5.
To probe the reaction mechanism, control experiments were performed. The reaction yields dropped significantly in the presence of radical scavengers such as butylated hydroxytoluene (BHT) and 2,2,6,6-tetramethylpiperidinyl 1-oxide (TEMPO), and a plausible reaction mechanism was proposed, as shown in Scheme 2. First, under visible-light irradiation, the diselenide is homolytically cleaved to produce a selenium radical 4a, which subsequently attacks the triple bond position of compound 3 to obtain radical intermediate 7. The final radical 7 is obtained as intermediate 8 by intramolecular cyclization. The intermediate 8 undergoes an oxidative de-aromatization reaction in an oxygen environment to obtain the desired product 5. In 2017, an efficient photocatalyst-free approach for the preparation of seleniumsubstituted spiro [4,5] trienones based on visible-light-induced selenium radical cyclization of N-aryl alkynamides was described by Baidya and coworkers (Scheme 2) [25]. Diverse N-aryl alkynamides and diaryl diselenides bearing electron-donating as well as electronwithdrawing groups in an aryl ring achieved the products under an oxygen atmosphere at room temperature. In addition, good yields were achieved in gram-scale reactions. A spiro-ring-opening strategy was realized to give fully substituted acryl amides 5. droxytoluene (BHT) and 2,2,6,6-tetramethylpiperidinyl 1-oxide (TEMPO), and a plausible reaction mechanism was proposed, as shown in Scheme 2. First, under visible-light irradiation, the diselenide is homolytically cleaved to produce a selenium radical 4a, which subsequently attacks the triple bond position of compound 3 to obtain radical intermediate 7. The final radical 7 is obtained as intermediate 8 by intramolecular cyclization. The intermediate 8 undergoes an oxidative de-aromatization reaction in an oxygen environment to obtain the desired product 5. Scheme 2. Visible-light-promoted synthesis of spiro [4,5] trienones.
To probe the reaction mechanism, control experiments were performed. The reaction yields dropped significantly in the presence of radical scavengers such as butylated hydroxytoluene (BHT) and 2,2,6,6-tetramethylpiperidinyl 1-oxide (TEMPO), and a plausible reaction mechanism was proposed, as shown in Scheme 2. First, under visible-light irradiation, the diselenide is homolytically cleaved to produce a selenium radical 4a, which subsequently attacks the triple bond position of compound 3 to obtain radical intermediate 7.
The final radical 7 is obtained as intermediate 8 by intramolecular cyclization. The intermediate 8 undergoes an oxidative de-aromatization reaction in an oxygen environment to obtain the desired product 5.
In 2019, Xu and coworkers reported an Se radical-triggered multi-component tandem cyclization of alkyne-tethered cyclohexadienones 11 and diaryl diselenides 12 under the irradiation of 25 W white LEDs at 40 • C (Scheme 3) [26]. The cascade cyclization starts with the addition of selenyl radical 12a to the alkyne, generating a vinylic radical 14, and proceeds in a 5-exo-trig fashion to 15, with the formation of the C−C bond. The intermediate 15 captures another selenyl radical, 12a, yielding bis-selenyl chromenones 15a. In the presence of water and a base, the final step of nucleophilic substitution affords compound 13. Therefore, in the absence of a base, the authors obtained the bis-selenyl derivatives 15a.
cyclization of alkyne-tethered cyclohexadienones 11 and diaryl diselenides 12 under the irradiation of 25 W white LEDs at 40 °C (Scheme 3) [26]. The cascade cyclization starts with the addition of selenyl radical 12a to the alkyne, generating a vinylic radical 14, and proceeds in a 5-exo-trig fashion to 15, with the formation of the C−C bond. The intermediate 15 captures another selenyl radical, 12a, yielding bis-selenyl chromenones 15a. In the presence of water and a base, the final step of nucleophilic substitution affords compound 13. Therefore, in the absence of a base, the authors obtained the bis-selenyl derivatives 15a. Scheme 3. Visible-light-induced cascade reaction of alkyne-tethered cyclohexadienones and diselenides.
In the same year, Kim et al. developed a practical method to synthesize selenated cyclopentanone derivatives 17 by photooxidation-catalyzed selenation through a ring expansion reaction with diselenides and alkenyl cyclobutanol derivatives (Scheme 4) [27]. A simple method was provided for the preparation of selenated cyclopentanone derivatives. The reaction occurred in acetonitrile solvent and was irradiated with blue light in air for 11 h. Ru(bpy)3Cl2·6H2O was used as a photocatalyst, with a yield of up to 94%. The authors performed a series of relevant control experiments to verify the mechanism of this reaction. The report described how the formation of the product was significantly inhibited by the addition of the radical scavenger TEMPO under standard conditions, demonstrating that the transformation involved a radical pathway. The authors proposed the reaction Scheme 3. Visible-light-induced cascade reaction of alkyne-tethered cyclohexadienones and diselenides.
In the same year, Kim et al. developed a practical method to synthesize selenated cyclopentanone derivatives 17 by photooxidation-catalyzed selenation through a ring expansion reaction with diselenides and alkenyl cyclobutanol derivatives (Scheme 4) [27]. A simple method was provided for the preparation of selenated cyclopentanone derivatives. The reaction occurred in acetonitrile solvent and was irradiated with blue light in air for 11 h. Ru(bpy) 3 Cl 2· 6H 2 O was used as a photocatalyst, with a yield of up to 94%. The authors performed a series of relevant control experiments to verify the mechanism of this reaction. The report described how the formation of the product was significantly inhibited by the addition of the radical scavenger TEMPO under standard conditions, demonstrating that the transformation involved a radical pathway. The authors proposed the reaction mechanism shown in Scheme 4. For example, the photocatalyst Ru(bpy) 3  Alternatively, radical 19 can be oxidized by oxygen to the selenium cation 20, which reacts with 1-(1-phenylethenyl)cyclobutanol 16 to give the corresponding cation 22 (path b). mechanism shown in Scheme 4. For example, the photocatalyst Ru(bpy)3Cl2·6H2O is converted to the excited state [Ru(bpy)3Cl2·6H2O]* under visible-light irradiation. Afterwards, the selenium radical 19 reacts with 1-(1-phenylvinyl)cyclobutanol 16 to give the carbon radical 21, which is oxidized by oxygen to the cationic intermediate 22 (path a). By 1,2alkyl migration of intermediate 21, the alcohol rearranges to form cyclopentanone 17. Alternatively, radical 19 can be oxidized by oxygen to the selenium cation 20, which reacts with 1-(1-phenylethenyl)cyclobutanol 16 to give the corresponding cation 22 (path b). In 2020, the Yang group disclosed a visible-light-induced, catalyst-free, and metalfree method for the construction of 4-sulfo/seleno-α,α-difluoro-γ-lactams via radical-initiated tandem cyclization (Scheme 5) [28]. In this process, 23 reacts smoothly with diphenyl disulfides under irradiation with 30 W blue LEDs, with K2HPO4 as a base to afford the desired products at room temperature. It is worth mentioning that the addition of Ru(bpy)3PF6 or Ir(ppy)2(dtbbpy)PF6 resulted in relatively lower yields of 39%. Control experiments demonstrated that visible light was vital for this transformation. Interestingly, for this photoinduced transformation, the 5-exo-trig cyclization dominated the process, and no 6-endo-trig cyclization product was isolated. This protocol exhibits good functional group tolerance and affords a variety of 4-thio-and 4-seleno-substituted 3,3-difluoro-γlactams in moderate to good yields. To gain insight into the mechanisms underlying this reaction, a series of control experiments were conducted. The addition of TEMPO suppressed the reaction and generated the addition compounds TEMPO−23 and TEMPO−18. The results of emission quenching experiments indicated that it is impossible to form the corresponding electron-donor-acceptor complexes for substrates 23 and 18. Based on In 2020, the Yang group disclosed a visible-light-induced, catalyst-free, and metal-free method for the construction of 4-sulfo/seleno-α,α-difluoro-γ-lactams via radical-initiated tandem cyclization (Scheme 5) [28]. In this process, 23 reacts smoothly with diphenyl disulfides under irradiation with 30 W blue LEDs, with K 2 HPO 4 as a base to afford the desired products at room temperature. It is worth mentioning that the addition of Ru(bpy) 3 PF 6 or Ir(ppy) 2 (dtbbpy)PF 6 resulted in relatively lower yields of 39%. Control experiments demonstrated that visible light was vital for this transformation. Interestingly, for this photoinduced transformation, the 5-exo-trig cyclization dominated the process, and no 6-endo-trig cyclization product was isolated. This protocol exhibits good functional group tolerance and affords a variety of 4-thio-and 4-seleno-substituted 3,3-difluoro-γ-lactams in moderate to good yields. To gain insight into the mechanisms underlying this reaction, a series of control experiments were conducted. The addition of TEMPO suppressed the reaction and generated the addition compounds TEMPO−23 and TEMPO−18. The results of emission quenching experiments indicated that it is impossible to form the corresponding electron-donor-acceptor complexes for substrates 23 and 18. Based on these results, a feasible mechanism for this reaction was proposed (Scheme 5). Initially, the radicals Ph−X • and Ph−XBr are generated under visible-light irradiation. The consumption of Ph-XBr by the base also promotes this transformation. The radical Ph-X • then abstracts the bromine atom from substrate 23 to offer the radical intermediate 25, which undergoes rapid 5-exo-trig cyclization to form the radical 26. Ultimately, the radical 26 and Ph−X • easily form the target 24 via radical-radical cross-coupling. Another radical pathway could not be completely excluded, as indicated by the combination of products detected. the radicals Ph−X • and Ph−XBr are generated under visible-light irradiation. The consumption of Ph-XBr by the base also promotes this transformation. The radical Ph-X • then abstracts the bromine atom from substrate 23 to offer the radical intermediate 25, which undergoes rapid 5-exo-trig cyclization to form the radical 26. Ultimately, the radical 26 and Ph−X • easily form the target 24 via radical-radical cross-coupling. Another radical pathway could not be completely excluded, as indicated by the combination of products detected.
In 2020, Reuter's group [29] reported the visible-light-assisted dearomatic carbon selenide iodine cyclization of aromatic homologues (Scheme 6). At different temperatures, alkynones can deliver selenized cyclohexadienones and spiro diepoxides. The reaction mixture was exposed to blue LED illumination at 18 °C, using acetonitrile as solvent. Starting from 1,4-diphenylbut-3-yn-2-one 27 and diphenyl diselenides as the selenium source, selenospiro-cyclohexadienones were obtained using oxygen in up to 88% yield. In addition, experimental studies on free radical control confirmed that the process proceeds through the free radical pathway. The mechanism was rationally described based on control experiments and competition experiments, as shown in Scheme 6. Namely, the addition of aryl selenium radical 4a produced under blue LED irradiation to the alkyne bond of 27 produces vinyl radicals 29, which subsequently undergo intramolecular cyclization to give intermediate 30.
In an oxygen environment, intermediate 30 undergoes peroxidation and is converted to the peroxy intermediate 31, which finally provides spirocyclized cyclic alkenones 28 together with an OH radical. Two OH radicals combine to deliver hydrogen peroxide followed by in situ generations of benzeneperoxyseleninic acid 33 in the In 2020, Reuter's group [29] reported the visible-light-assisted dearomatic carbon selenide iodine cyclization of aromatic homologues (Scheme 6). At different temperatures, alkynones can deliver selenized cyclohexadienones and spiro diepoxides. The reaction mixture was exposed to blue LED illumination at 18 • C, using acetonitrile as solvent. Starting from 1,4-diphenylbut-3-yn-2-one 27 and diphenyl diselenides as the selenium source, selenospiro-cyclohexadienones were obtained using oxygen in up to 88% yield. In addition, experimental studies on free radical control confirmed that the process proceeds through the free radical pathway. The mechanism was rationally described based on control experiments and competition experiments, as shown in Scheme 6. Namely, the addition of aryl selenium radical 4a produced under blue LED irradiation to the alkyne bond of 27 produces vinyl radicals 29, which subsequently undergo intramolecular cyclization to give intermediate 30.
In an oxygen environment, intermediate 30 undergoes peroxidation and is converted to the peroxy intermediate 31, which finally provides spirocyclized cyclic alkenones 28 together with an OH radical. Two OH radicals combine to deliver hydrogen peroxide followed by in situ generations of benzeneperoxyseleninic acid 33 in the presence of diaryl diselenide 4, which functions as an epoxidizing agent. The spiro-cyclized cyclic enone 28 undergoes double epoxidation with the in situ-generated epoxidizing agent 33, facilitating the epoxidation of the adjacent enones to the di-epoxide 32.
Molecules 2023, 28, x FOR PEER REVIEW 9 of 38 presence of diaryl diselenide 4, which functions as an epoxidizing agent. The spiro-cyclized cyclic enone 28 undergoes double epoxidation with the in situ-generated epoxidizing agent 33, facilitating the epoxidation of the adjacent enones to the di-epoxide 32. In 2020, Xu and coworkers further developed the visible-light-induced selenocyclization reaction of indolyl-ynones 30 with diselenides at room temperature under an air atmosphere (Scheme 7) [30]. Diverse 3-selenospiroindolenines bearing various functional groups were obtained in moderate to good yields. Similarly, a phenylselenyl free radical is generated from diphenyl diselenide under visible-light irradiation. The desired product is then obtained through the radical addition/oxidation/deprotonation pathway.
Based on free-radical verification experiments and previous literature reviews, Scheme 7 proposes and describes two possible pathways. The irradiation of diphenyl Scheme 6. Spirocyclization of homologated-ynones.
In 2020, Xu and coworkers further developed the visible-light-induced selenocyclization reaction of indolyl-ynones 30 with diselenides at room temperature under an air atmosphere (Scheme 7) [30]. Diverse 3-selenospiroindolenines bearing various functional groups were obtained in moderate to good yields. Similarly, a phenylselenyl free radical is generated from diphenyl diselenide under visible-light irradiation. The desired product is then obtained through the radical addition/oxidation/deprotonation pathway. ynones 34 to the phenylselenyl radical 19 affords an alkenyl radical 36, followed by cyclizing with the indole at its 3-position to form a spirocyclic radical intermediate 37.
Oxidation of 37 to 38 in air then undergoes dehydrogenation in base conditions to afford the desired product 35. In path b, the reaction proceeds by oxidation of the phenylselenyl radical 19 to PhSe + in air, which reacts with the alkyne group of indolyl-ynone 34, leading to the formation of seleniumion. Then, cyclization at the 3-position of indole gives the desired product 35. Scheme 7. Visible-light-promoted synthesis of 3-selenospiroindolenines.
Very recently, Wang disclosed a regio-and chemoselective radical cascade cyclization of 1,6-enynes 39 and areneselenosulfonates 40 under 34 W blue LED irradiation in the air without any photocatalysts (Scheme 8) [31]. Numerous substrates 39 were examined, and the corresponding cyclized products 41 were obtained in good to excellent yields. This reaction also proceeded smoothly using diaryldiselenides 40 with 1,6-enynes and Based on free-radical verification experiments and previous literature reviews, Scheme 7 proposes and describes two possible pathways. The irradiation of diphenyl diselenide 18 produces phenylselenyl free radical 19. In path a, the addition of indolyl-ynones 34 to the phenylselenyl radical 19 affords an alkenyl radical 36, followed by cyclizing with the indole at its 3-position to form a spirocyclic radical intermediate 37.
Oxidation of 37 to 38 in air then undergoes dehydrogenation in base conditions to afford the desired product 35. In path b, the reaction proceeds by oxidation of the phenylselenyl radical 19 to PhSe + in air, which reacts with the alkyne group of indolyl-ynone 34, leading to the formation of seleniumion. Then, cyclization at the 3-position of indole gives the desired product 35.
Very recently, Wang disclosed a regio-and chemoselective radical cascade cyclization of 1,6-enynes 39 and areneselenosulfonates 40 under 34 W blue LED irradiation in the air without any photocatalysts (Scheme 8) [31]. Numerous substrates 39 were examined, and the corresponding cyclized products 41 were obtained in good to excellent yields. This reaction also proceeded smoothly using diaryldiselenides 40 with 1,6-enynes and produced the desired products with moderate to good yields. However, this method was not applicable when the chain length was increased from one to two or three. The internal alkene and free amine in enyne were also not tolerant of this transformation. This protocol offers an effective approach to building selenium-substituted pyrrolidine derivatives via multiple chemical bond constructions in a 5-exo-dig fashion, including one C-S bond, one C-Se bond, and one C-C bond.
Molecules 2023, 28, x FOR PEER REVIEW 11 of 38 produced the desired products with moderate to good yields. However, this method was not applicable when the chain length was increased from one to two or three. The internal alkene and free amine in enyne were also not tolerant of this transformation. This protocol offers an effective approach to building selenium-substituted pyrrolidine derivatives via multiple chemical bond constructions in a 5-exo-dig fashion, including one C-S bond, one C-Se bond, and one C-C bond.
Notably, the cyclization reaction does not require photocatalysts or other additives. The bond energy of the Se-Se bond allows the production of photoinduced phase Se radicals and is further used in a wide range of reactions. In 2020, Tran and colleagues reported the synthesis of diselenyl quinoxalate 44 from o-diisocyanate arenes 42 and diaryl or dialkyl diselenides 43 with moderate to good yields (Scheme 9) [32].
The addition of the radical inhibitor TEMPO under the standard reaction suggested that the transformation involved a radical process. Control experiments also showed that diselenides were activated through a photocatalytic energy transfer pathway. Based on the results of relevant control experiments and previous references, two possible mechanisms have been depicted, as shown in Scheme 9. The first mechanism involves a photoinduced aza-Bergman-type cyclization followed by trapping of the 11 species (path A). In the second mechanism (path B), the R 2 Se radical species 43a attacks the isocyanide group to form the imidoyl radical intermediate 42a, followed by intramolecular addition to the vicinal isocyanide group. Finally, intermediate 45 reacts with another equivalent of diorganoyl diselenide, R 2 Se 43a, affording the bis-selenylquinoxalines 44. Notably, the cyclization reaction does not require photocatalysts or other additives. The bond energy of the Se-Se bond allows the production of photoinduced phase Se radicals and is further used in a wide range of reactions. In 2020, Tran and colleagues reported the synthesis of diselenyl quinoxalate 44 from o-diisocyanate arenes 42 and diaryl or dialkyl diselenides 43 with moderate to good yields (Scheme 9) [32].
The addition of the radical inhibitor TEMPO under the standard reaction suggested that the transformation involved a radical process. Control experiments also showed that diselenides were activated through a photocatalytic energy transfer pathway. Based on the results of relevant control experiments and previous references, two possible mechanisms have been depicted, as shown in Scheme 9. The first mechanism involves a photoinduced aza-Bergman-type cyclization followed by trapping of the 11 species (path A). In the second mechanism (path B), the R 2 Se radical species 43a attacks the isocyanide group to form the imidoyl radical intermediate 42a, followed by intramolecular addition to the vicinal isocyanide group. Finally, intermediate 45 reacts with another equivalent of diorganoyl diselenide, R 2 Se 43a, affording the bis-selenylquinoxalines 44.
In 2021, Zhu and colleagues [33] described a visible-light-mediated diaryl selenide cyclization of 1,6-enylene 46 with diselenides ether radical cyclization (Scheme 10). It is proved that terminal alkyne and inner alkyne derived from 1,6-enylene are suitable for this synthesis, and the cyclized product 47 with a good yield is obtained. Through validation experiments based on free radicals, the mechanism of radical cyclization is proposed. First, diaryl diethers 18 produce aryl selenium radicals 19 under visible-light irradiation. Then, a selenium free radical 19 is added to the carbon-carbon triple bond of alkyne 46 to form a carbon radical intermediate 48. Then the intermediate vinyl free radical 48 undergoes an intramolecular 5-external triangular cyclization reaction to generate a tertiary carbon-alkyl radical 49. Finally, the diselenium compound is captured by radical 49 to obtain the target product 47 and the aryl selenyl radical 19. In 2021, Zhu and colleagues [33] described a visible-light-mediated diaryl selenide cyclization of 1,6-enylene 46 with diselenides ether radical cyclization (Scheme 10). It is proved that terminal alkyne and inner alkyne derived from 1,6-enylene are suitable for this synthesis, and the cyclized product 47 with a good yield is obtained. Through validation experiments based on free radicals, the mechanism of radical cyclization is proposed. In 2017, Wang's group [34] developed a simple and effective scheme for the preparation of indoles using H2O2 and visible light to drive the reaction of 2-alkynyl aniline with disulfides. The corresponding products were synthesized at room temperature with high yields and without additional conditions. In the same year, another method was pub-Scheme 10. Photoinduced regio-and chemoselective radical cyclization of unactivated 1,6-enynes with selenides.

Cyclization of Disulfides with Alkenes and Alkynes
In 2017, Wang's group [34] developed a simple and effective scheme for the preparation of indoles using H 2 O 2 and visible light to drive the reaction of 2-alkynyl aniline with disulfides. The corresponding products were synthesized at room temperature with high yields and without additional conditions. In the same year, another method was published for the preparation of benzothiophenes, which was achieved by visible-light induction of oalkynyl anilines and disulfides without the addition of metals or photocatalysts (Scheme 11). The reaction offers good yields, broad substrate expansion, and simple operating conditions. Benzofuran-like scaffolds are usually found in natural products and display biological and pharmaceutical activity. In 2021, Li's group [35] developed a simple and effective method for the visible-light-induced tandem cyclization of 1,6-benzenes with disulfides for the synthesis of functionalized benzofurans (Scheme 12). Scheme 11. Synthesis of benzo heterocycles.
Benzofuran-like scaffolds are usually found in natural products and display biological and pharmaceutical activity. In 2021, Li's group [35] developed a simple and effective method for the visible-light-induced tandem cyclization of 1,6-benzenes with disulfides for the synthesis of functionalized benzofurans (Scheme 12).
The reaction proceeded smoothly under metal-free conditions in room-temperature air, providing the desired products with broad functional group tolerance and good yields. On the basis of experiments verified by radicals, the authors propose a plausible mechanism, as shown in Scheme 12. On the one hand, PC (Mes-Acr-Me-ClO 4 ) is transformed into the excited state PC* under visible-light irradiation, which is subsequently oxidized by oxygen to PC + while generating superoxide radical anions [36]. In the presence of Nmethyl-2-pyrrolidone (NMP), PC + again becomes PC in the catalytic cycle. On the other hand, the superoxide radical anion is added to the alkyne 56 to provide the alkyne radical anion 59, which reacts with diphenyl disulfide 57 to produce the peroxyalkynyl sulfide The reaction proceeded smoothly under metal-free conditions in room-temperature air, providing the desired products with broad functional group tolerance and good yields. On the basis of experiments verified by radicals, the authors propose a plausible mechanism, as shown in Scheme 12. On the one hand, PC (Mes-Acr-Me-ClO4) is transformed into the excited state PC* under visible-light irradiation, which is subsequently oxidized by oxygen to PC + while generating superoxide radical anions [36]. In the presence of N-methyl-2-pyrrolidone (NMP), PC + again becomes PC in the catalytic cycle. On the other hand, the superoxide radical anion is added to the alkyne 56 to provide the alkyne radical anion 59, which reacts with diphenyl disulfide 57 to produce the peroxyalkynyl sulfide

Direct Selenylation/Sulfuration of C−H Bonds
Coumarins form a well-known class of naturally occurring heteroarenes, which exhibit a diverse range of biological and medicinal activity, including anticancer, antibacterial, and anticoagulant properties [37]. Their use in materials science is also well established [38]. In 2018, Yang and colleagues [39] reported the photoinduced C(sp 2 )−H selenium functionalization of 4-amino-substituted coumarins 63 in the presence of ammonium persulfate (Scheme 13). Under optimal conditions, various 4-amino-substituted coumarin derivatives were found to be converted to the desired products with diselenides in moderate to good yields; unfortunately, 2H-chromen-2-one is not suitable for this visible-light-induced selenization reaction. Although the mechanism of the visible-light-induced selenization pathway remains unclear, Scheme 13 proposes two possible routes based on radical verification experiments and previous literature reports [40][41][42]. First, (NH 4 ) 2 S 2 O 8 is irradiated with visible light to give the reactive radical anion SO 4 •− . Then, a single-electron transfer process occurs between 63 and SO 4 •− to give the corresponding radical intermediate 63a. •− to give the corresponding radical cation 69. The use of inexpensive and readily available organic dyes as photocatalysts has attracted extensive attention in the synthesis community [43]. In 2018, Braga and colleagues reported a more environmentally friendly, photoinduced synthesis of selenium aromatic compounds 71 (Scheme 14). Under visible-light irradiation, using rose bengal (RB) as the photocatalyst and air as the terminal oxidant, the indole was selenized with a half molar equivalent of diselenide to obtain a selenium-containing indole compound in good yield. The reaction has broad functional group tolerance and is also applicable to a variety of heterocycles, including indazole, imidazopyridine, imidazolyl, and imidazothiazole, as well as aniline, anisole, β-naphthylamine, and β-naphthol, for example. Validation experiments based on free radicals allowed the authors to propose a possible reaction mechanism. The use of inexpensive and readily available organic dyes as photocatalysts has attracted extensive attention in the synthesis community [43]. In 2018, Braga and colleagues reported a more environmentally friendly, photoinduced synthesis of selenium aromatic compounds 71 (Scheme 14). Under visible-light irradiation, using rose bengal (RB) as the photocatalyst and air as the terminal oxidant, the indole was selenized with a half molar equivalent of diselenide to obtain a selenium-containing indole compound in good yield. The reaction has broad functional group tolerance and is also applicable to a variety of heterocycles, including indazole, imidazopyridine, imidazolyl, and imidazothiazole, as well as aniline, anisole, β-naphthylamine, and β-naphthol, for example. Validation experiments based on free radicals allowed the authors to propose a possible reaction mechanism. In 2019, Lemir's group published a method for synthesizing 3-selenoindoles from diselenides and indoles or electron-rich olefins as raw materials and ethanol as a green solvent (Scheme 15) [44]. By this simple and environmentally friendly method, several 3selenoindoles and many asymmetric diselenides can be obtained in high yields. In contrast, indoles with electron-withdrawing groups do not react. In 2019, Lemir's group published a method for synthesizing 3-selenoindoles from diselenides and indoles or electron-rich olefins as raw materials and ethanol as a green solvent (Scheme 15) [44]. By this simple and environmentally friendly method, several 3selenoindoles and many asymmetric diselenides can be obtained in high yields. In contrast, indoles with electron-withdrawing groups do not react. Recently, α-selenoketones have attracted attention due to their versatile applications in organic synthesis as well as their biological activity in the treatment of disorders such as depression and anxiety [45]. Most of the α-selenofunctionalization protocols include the in situ generation of nucleophilic selenium reagents or previous formation of an electrophilic species from diselenides. In 2020, Schneider [46] reported an efficient photoinduced α-selenide reaction of ketones without metal additives or photosensitizers, providing a green scheme for the synthesis of various α-selenide ketones using light energy (Scheme 16). In this experiment, α-selenide ketones were prepared using equal amounts of diselenides and alkyl ketones 76 under compact florescent lamp ultraviolet A (CFL UVA) irradiation at 26 W for 6 h with 20 mol% pyrrolidine as the organocatalyst and CH3CN as solvent. Subsequently, the universality of the substrate was explored, and it was found that when the diorganodiselenide and the cyclic and acyclic ketones had different substituents, the reaction could proceed smoothly to create a series of α-selenide products with moderate to excellent yields. These findings demonstrate the generality of the method.
The addition of the radical inhibitor TEMPO to the standard reaction suggests that the transformation involves a radical process. Control experiments also showed that diselenide is activated through a photocatalytic energy transfer pathway. Based on the results of relevant control experiments and previous references, a possible mechanism was depicted, as shown in Scheme 16. Recently, α-selenoketones have attracted attention due to their versatile applications in organic synthesis as well as their biological activity in the treatment of disorders such as depression and anxiety [45]. Most of the α-selenofunctionalization protocols include the in situ generation of nucleophilic selenium reagents or previous formation of an electrophilic species from diselenides. In 2020, Schneider [46] reported an efficient photoinduced αselenide reaction of ketones without metal additives or photosensitizers, providing a green scheme for the synthesis of various α-selenide ketones using light energy (Scheme 16). In this experiment, α-selenide ketones were prepared using equal amounts of diselenides and alkyl ketones 76 under compact florescent lamp ultraviolet A (CFL UVA) irradiation at 26 W for 6 h with 20 mol% pyrrolidine as the organocatalyst and CH 3 CN as solvent. Subsequently, the universality of the substrate was explored, and it was found that when the diorganodiselenide and the cyclic and acyclic ketones had different substituents, the reaction could proceed smoothly to create a series of α-selenide products with moderate to excellent yields. These findings demonstrate the generality of the method.
The addition of the radical inhibitor TEMPO to the standard reaction suggests that the transformation involves a radical process. Control experiments also showed that diselenide is activated through a photocatalytic energy transfer pathway. Based on the results of relevant control experiments and previous references, a possible mechanism was depicted, as shown in Scheme 16. In 2022, Choudhury et al. [47] reported a visible-light-mediated C(sp 2 )−H selenation reaction of aminopyrazoles (Scheme 17). The authors chose 5-amino-3-methyl-1H-phenylpyrazoles 83 and diphenyl diselenides as model substrates and demonstrated experimentally that the reaction does not require additional metal oxidants; only 12 h of visiblelight irradiation in nitrogen at room temperature is required to obtain the desired target products. The reaction also exhibits broad substrate versatility with moderate to good yields and is also suitable for gram-scale synthesis. Finally, the reaction provides important pharmaceutical heterocyclic compounds such as aminopyrazoles, isoxazoles, isothiazoles, and selenium uridines pyrimidines. In 2022, Choudhury et al. [47] reported a visible-light-mediated C(sp 2 )−H selenation reaction of aminopyrazoles (Scheme 17). The authors chose 5-amino-3-methyl-1Hphenylpyrazoles 83 and diphenyl diselenides as model substrates and demonstrated experimentally that the reaction does not require additional metal oxidants; only 12 h of visible-light irradiation in nitrogen at room temperature is required to obtain the desired target products. The reaction also exhibits broad substrate versatility with moderate to good yields and is also suitable for gram-scale synthesis. Finally, the reaction provides important pharmaceutical heterocyclic compounds such as aminopyrazoles, isoxazoles, isothiazoles, and selenium uridines pyrimidines. Organosulfur compounds are widely used in medicine, pesticides, new materials, and other fields. Therefore, it is very important to develop new methods for the formation of carbon-sulfur bonds. A reaction strategy for the generation of sulfur radicals from disulfides catalyzed by visible-light has been rapidly developed, and the direct sulfurization of carbon-hydrogen bonds has been widely used. In 2016, Wang's group [48]  Organosulfur compounds are widely used in medicine, pesticides, new materials, and other fields. Therefore, it is very important to develop new methods for the formation of carbon-sulfur bonds. A reaction strategy for the generation of sulfur radicals from disulfides catalyzed by visible-light has been rapidly developed, and the direct sulfurization of carbon-hydrogen bonds has been widely used. In 2016, Wang's group [48] developed a simple and effective method for the preparation of α-aryl thioethers by direct thiolysis at α-C(sp 3 )−H of ethers under visible-light induction using acridine red as a novel photocatalyst (Scheme 18). For this reaction, diphenyldisulfide 88 and tetrahydrofuran 89 were selected as model substrates, acetone as the solvent, and TBHP as the oxidant. When the reaction is irradiated with green light for 12 h at room temperature, the target product 90 can be obtained with a good yield. as shown in Scheme 18. First, the AR in the ground state becomes AR* in the excited state under green light irradiation, which is highly reductive. Subsequent interaction with the oxide t BuOOH (TBHP) gives a hydroxyl radical HO • and a tert-butoxy radical t BuO • , while AR* is transformed into the ground state AR. Subsequently, HO • or t BuO • plucks a hydrogen from tetrahydrofuran (THF) to give the key alkoxy radical intermediate 91. Intermediate 91 reacts with PhSSPh 88a to give the desired product 2-(phenylthio)-tetrahydrofuran 90a and a new radical PhS • .

Scheme 18. Visible-light-induced direct thiolation of ether with disulfides at α-C(sp 3 )−H.
In 2019, the Kumar group disclosed an attractive mild visible-light-induced strategy for the organo-chalcogenylation (S, Se) of indole in an oxygen atmosphere using commercially available substrates in acetone (Scheme 19) [49]. Further, cyclic voltammetry, UVvisible analysis, and electron paramagnetic resonance (EPR) spectroscopic studies have been carried out to establish the mechanism of the light-induced reaction.

Scheme 18. Visible-light-induced direct thiolation of ether with disulfides at α-C(sp 3 )−H.
According to the free radical experiment results, the authors propose a mechanism, as shown in Scheme 18. First, the AR in the ground state becomes AR* in the excited state under green light irradiation, which is highly reductive. Subsequent interaction with the oxide t BuOOH (TBHP) gives a hydroxyl radical HO • and a tert-butoxy radical t BuO • , while AR* is transformed into the ground state AR. Subsequently, HO • or t BuO • plucks a hydrogen from tetrahydrofuran (THF) to give the key alkoxy radical intermediate 91.
Intermediate 91 reacts with PhSSPh 88a to give the desired product 2-(phenylthio)tetrahydrofuran 90a and a new radical PhS • .
In 2019, the Kumar group disclosed an attractive mild visible-light-induced strategy for the organo-chalcogenylation (S, Se) of indole in an oxygen atmosphere using commercially available substrates in acetone (Scheme 19) [49]. Further, cyclic voltammetry, UV-visible analysis, and electron paramagnetic resonance (EPR) spectroscopic studies have been carried out to establish the mechanism of the light-induced reaction.
Although allyl sulfides are widely used, the direct-catalyzed allyl C(sp 3 )−H sulfidation reaction remains unclear. In 2020, Hong et al. [50] reported a direct photooxidationcatalyzed allyl C(sp 3 )−H sulfidation reaction by visible-light (Scheme 20). The authors initially optimized the reaction conditions using disulfides 97 and 2,3-dimethyl-2-butene 98 as model substrates. The results showed that high yields of allyl sulfides 99 were obtained with 2.0 mol% (CF 3 ppy) 3 as the catalyst, sodium hydroxide as the oxidant, and dimethylacetamide (DMA) as the solvent under 40 W blue LEDs irradiation for 24 h. In addition, the authors explored the universality of the substrate, and discovered that these reaction conditions were unfortunately not applicable to dialkyl disulfides, with only the corresponding thiols obtained. However, the authors proposed a feasible mechanism for the reaction. First, the sulfur group produced by the interaction of disulfides with an iridium catalyst under light may induce a single-electron transfer of allyl C(sp 3 )−H to obtain allyl radicals, which then undergo radical coupling with the disulfide. In addition, a redox process may occur in the presence of a photocatalyst in which the allyl radical is oxidized to a cationic intermediate, which is ionically coupled to the thioaryl anion to obtain the target product. Although allyl sulfides are widely used, the direct-catalyzed allyl C(sp 3 )−H sulfidation reaction remains unclear. In 2020, Hong et al. [50] reported a direct photooxidationcatalyzed allyl C(sp 3 )−H sulfidation reaction by visible-light (Scheme 20). The authors initially optimized the reaction conditions using disulfides 97 and 2,3-dimethyl-2-butene 98 as model substrates. The results showed that high yields of allyl sulfides 99 were obtained with 2.0 mol% (CF3ppy)3 as the catalyst, sodium hydroxide as the oxidant, and dimethylacetamide (DMA) as the solvent under 40 W blue LEDs irradiation for 24 h. In addition, the authors explored the universality of the substrate, and discovered that these reaction conditions were unfortunately not applicable to dialkyl disulfides, with only the corresponding thiols obtained. However, the authors proposed a feasible mechanism for the reaction. First, the sulfur group produced by the interaction of disulfides with an iridium catalyst under light may induce a single-electron transfer of allyl C(sp 3 )−H to obtain allyl radicals, which then undergo radical coupling with the disulfide. In addition, a redox process may occur in the presence of a photocatalyst in which the allyl radical is oxidized to a cationic intermediate, which is ionically coupled to the thioaryl anion to obtain the target product. Recently, in 2020, the Glorius group published a photocatalytic dithioether reaction for the simple hydrogen methane-thionation of olefins without gaseous and toxic methane-thionate (Scheme 21) [51]. Fortunately, when the reaction uses 100 as a substrate, the reaction requires only the substitution of the thiol coupling with dimethyl disulfide Recently, in 2020, the Glorius group published a photocatalytic dithioether reaction for the simple hydrogen methane-thionation of olefins without gaseous and toxic methanethionate (Scheme 21) [51]. Fortunately, when the reaction uses 100 as a substrate, the reaction requires only the substitution of the thiol coupling with dimethyl disulfide and illumination with a blue light in DMA solvent for 16 h to give the desired product in a very good yield [52,53]. In addition, the reaction is also feasible for tribromoimidazole and 5-chloro-2-aminothiazole, demonstrating the suitability of the methanethiol scheme for a variety of structures.

Scheme 20. Direct thiolation of allyl C(sp 3 )−H.
Recently, in 2020, the Glorius group published a photocatalytic dithioether reaction for the simple hydrogen methane-thionation of olefins without gaseous and toxic methane-thionate (Scheme 21) [51]. Fortunately, when the reaction uses 100 as a substrate, the reaction requires only the substitution of the thiol coupling with dimethyl disulfide and illumination with a blue light in DMA solvent for 16 h to give the desired product in a very good yield [52,53]. In addition, the reaction is also feasible for tribromoimidazole and 5-chloro-2-aminothiazole, demonstrating the suitability of the methanethiol scheme for a variety of structures.

Direct Selenylation of C−C Bonds
Selenium amino acids are important components for the synthesis of selenoproteins. However, there are few methods for the preparation of selenium amino acids. In 2016, Fu's group [54] reported a method for the preparation of α-selenamine-based compounds using N-Bis(Boc)-Asp(oPht)-oMe 103 and diphenyl diselenides 104 as a model substrate (Scheme 22). More importantly, this method enables the synthesis of a series of bioactive and chiral selenoamino acid derivatives. A rational mechanism for the synthesis of chiral α-selenoamino acids is proposed in Scheme 22. First, 103, Ru(bpy)3 2+ is irradiated by visible-light to the excited state [Ru(bpy)3 2+ ] * , which is reduced by diethyl 2,6-dimethyl-1,4-Scheme 21. Site-selective thiolation of (multi)halogenated heteroarenes.

Direct Selenylation of C−C Bonds
Selenium amino acids are important components for the synthesis of selenoproteins. However, there are few methods for the preparation of selenium amino acids. In 2016, Fu's group [54] reported a method for the preparation of α-selenamine-based compounds using N-Bis(Boc)-Asp(oPht)-oMe 103 and diphenyl diselenides 104 as a model substrate (Scheme 22). More importantly, this method enables the synthesis of a series of bioactive and chiral selenoamino acid derivatives. A rational mechanism for the synthesis of chiral α-selenoamino acids is proposed in Scheme 22. First, 103, Ru(bpy) 3 2+ is irradiated by visible-light to the excited state [Ru(bpy) 3 2+ ] * , which is reduced by diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate(HE) or N,N-diisopropylethylamine (DIPEA) to give Ru(bpy) 3+ , where HE or DIPEA became 106 or 106a. The subsequent interaction of Ru(bpy) 3+ with 103 gives the radical anion 103a and the regenerated catalyst Ru(bpy) 3 2+ , after which 103a is eliminated to give the benzodicarboximide anion 107 and carbon dioxide to give the radical 103b. Finally, 104a and 106 are subjected to free radical coupling to obtain the target product 105. 104a interacts with 106 and 107 to give 108, 109, and 110. dihydropyridine-3,5-dicarboxylate(HE) or N,N-diisopropylethylamine (DIPEA) to give Ru(bpy) 3+ , where HE or DIPEA became 106 or 106a. The subsequent interaction of Ru(bpy) 3+ with 103 gives the radical anion 103a and the regenerated catalyst Ru(bpy)3 2+ , after which 103a is eliminated to give the benzodicarboximide anion 107 and carbon dioxide to give the radical 103b. Finally, 104a and 106 are subjected to free radical coupling to obtain the target product 105. 104a interacts with 106 and 107 to give 108, 109, and 110. C−H bond activation is one of the most challenging topics in organic synthesis and has received extensive attention from chemists. Finding environmentally friendly catalyst systems for carbon-hydrogen bond activation to construct carbon-selenium bonds has important theoretical and practical value. In 2019, Zhou et al. described the photocatalytic vulcanization, selenization, and boration of cyclosterone oxime esters by the cleavage of C−C bonds initiated by imidamines (Scheme 23) [55]. In this method, using fac-Ir(ppy) 3 , diphenyl diselenides 112 and irradiation with blue LEDs several functionalized organoselenides 113 were prepared. Based on the experimental results and previous reports [56][57][58], a plausible mechanism is proposed whereby Ir(III) is converted to the strongly reduced excited state Ir(III)* under visible-light irradiation, reducing 111a to the imine group 114. The radical 114 is cleaved by the ring-opening C−C bond to generate the highly reactive cyanoalkyl radical 115, which is captured by disulfides, diselenides, and diborides, respectively, forming an sp 3 C−S bond and C−Se bond. The single electron transfer(SET) process of RX • reduction to Ir(IV) produces cation 112b, which regenerates Ir.
C−H bond activation is one of the most challenging topics in organic synthesis and has received extensive attention from chemists. Finding environmentally friendly catalyst systems for carbon-hydrogen bond activation to construct carbon-selenium bonds has important theoretical and practical value. In 2019, Zhou et al. described the photocatalytic vulcanization, selenization, and boration of cyclosterone oxime esters by the cleavage of C−C bonds initiated by imidamines (Scheme 23) [55]. In this method, using fac-Ir(ppy)3, diphenyl diselenides 112 and irradiation with blue LEDs several functionalized organoselenides 113 were prepared. Based on the experimental results and previous reports [56][57][58], a plausible mechanism is proposed whereby Ir(III) is converted to the strongly reduced excited state Ir(III)* under visible-light irradiation, reducing 111a to the imine group 114. The radical 114 is cleaved by the ring-opening C−C bond to generate the highly reactive cyanoalkyl radical 115, which is captured by disulfides, diselenides, and diborides, respectively, forming an sp 3 C−S bond and C−Se bond. The single electron transfer(SET) process of RX • reduction to Ir(IV) produces cation 112b, which regenerates Ir.

Direct Selenylation/Sulfuration of C−N Bonds
As a common chemical bond, C−N bonds widely exist in organic molecules, and the activation and breaking of C−N bonds play an important role in organic reactions and life chemistry. In 2020, Zhao [59] reported the substitution of azosulfone groups in heterocycles by organoselenide groups driven by blue LEDs. The method is also applicable to the preparation of selenide aromatics and organotelluride products (Scheme 24). The addition of the radical inhibitor TEMPO under standard reactions suggests that the transformation involves a radical process. The authors propose an initial mechanism whereby the (hetero)aryl substrate 116 becomes excited upon irradiation with visible light, followed by the decomposition of the azosulfone group to form the aryl radicals 119. Aryl radicals 119 with diselenides 117 affords the corresponding selenium-containing compound 118 and the organoselenides RY* group.
preparation of selenide aromatics and organotelluride products (Scheme 24). The addition of the radical inhibitor TEMPO under standard reactions suggests that the transformation involves a radical process. The authors propose an initial mechanism whereby the (hetero)aryl substrate 116 becomes excited upon irradiation with visible light, followed by the decomposition of the azosulfone group to form the aryl radicals 119. Aryl radicals 119 with diselenides 117 affords the corresponding selenium-containing compound 118 and the organoselenides RY* group. Scheme 24. Blue LEDs mediated seleno-substitutions of azosulfone group.
In the past few years, pyridinium salts have been widely used in organic synthesis as radical precursors due to their ability to reduce single-electron transfer [60]. These salts typically form new C−C, C−N, C−O, and C−B bonds via transition metal catalysis, photocatalysis, and Lewis base activation. However, the formation of carbon-chalcogen bonds by cleavage of pyridinium salts has not been reported to date [61][62][63]. In 2021, Zhao et al. [64] reported a method for the synthesis of asymmetric selenides from alkylpyridinium salts and diselenides under visible-light catalysis (Scheme 25). Radical verification experiments show that the reaction is a radical pathway. First, the authors chose benzyl Katritzky salt 120 and diselenide 12 as model substrates. The selenide product 121 was obtained by reacting with DIPEA as the oxidant and eosin Y as the photocatalyst in an acetonitrile solution at room temperature for 20 h. The reaction is germane to a wide range of applications. First, the excited state of eosin Y (EY*) is reduced by single-electron transfer 120 to yield a dihydropyridine radical 122, which subsequently decomposes into a benzyl radical 123 and an aromatized pyridine derivative 124. Single-electron reduction to EY + from DIPEA concurrently regenerates the ground-state eosin Y. Next, benzyl radical 123 reacts with diselenide 12 to give product 121. In the past few years, pyridinium salts have been widely used in organic synthesis as radical precursors due to their ability to reduce single-electron transfer [60]. These salts typically form new C−C, C−N, C−O, and C−B bonds via transition metal catalysis, photocatalysis, and Lewis base activation. However, the formation of carbon-chalcogen bonds by cleavage of pyridinium salts has not been reported to date [61][62][63]. In 2021, Zhao et al. [64] reported a method for the synthesis of asymmetric selenides from alkylpyridinium salts and diselenides under visible-light catalysis (Scheme 25). Radical verification experiments show that the reaction is a radical pathway. First, the authors chose benzyl Katritzky salt 120 and diselenide 12 as model substrates. The selenide product 121 was obtained by reacting with DIPEA as the oxidant and eosin Y as the photocatalyst in an acetonitrile solution at room temperature for 20 h. The reaction is germane to a wide range of applications. First, the excited state of eosin Y (EY*) is reduced by single-electron transfer 120 to yield a dihydropyridine radical 122, which subsequently decomposes into a benzyl radical 123 and an aromatized pyridine derivative 124. Single-electron reduction to EY + from DIPEA concurrently regenerates the ground-state eosin Y. Next, benzyl radical 123 reacts with diselenide 12 to give product 121.
In recent years, aryl hydrazides have attracted much attention as electrophilic substitutes in cross-coupling reactions. Aromatics can construct various chemical bonds, including C−C, [65] C−N, [66] C−S, [67] C−Se, [68] and C−P [69] bonds. In particular, aryl hydrazines can act as aryl reactants by releasing nitrogen gas. In 2019, Yu's group [70] reported the testing of the substrates phenylhydrazine 125 and diphenyl sulfide 126 using the organic dye Na 2 -eosin Y as the catalyst, hydrogen peroxide as the oxidant, and dimethyl sulfoxide (DMSO) as the optimal reaction conditions to yield the expected sulfide product 127 (Scheme 26). Under optimal conditions, they explored a range of visible-light-promoted hydrazine sulfides and showed that substrates with strong electron-absorbing groups were not converted to the corresponding sulfides with high efficiency. This may be due to the low reactivity of the corresponding radical intermediates. In recent years, aryl hydrazides have attracted much attention as electrophilic substitutes in cross-coupling reactions. Aromatics can construct various chemical bonds, including C−C, [65] C−N, [66] C−S, [67] C−Se, [68] and C−P [69] bonds. In particular, aryl hydrazines can act as aryl reactants by releasing nitrogen gas. In 2019, Yu's group [70] reported the testing of the substrates phenylhydrazine 125 and diphenyl sulfide 126 using the organic dye Na2-eosin Y as the catalyst, hydrogen peroxide as the oxidant, and dimethyl sulfoxide (DMSO) as the optimal reaction conditions to yield the expected sulfide product 127 (Scheme 26). Under optimal conditions, they explored a range of visible-light-promoted hydrazine sulfides and showed that substrates with strong electron-absorbing groups were not converted to the corresponding sulfides with high efficiency. This may be due to the low reactivity of the corresponding radical intermediates.
When the sulfidation reaction was carried out with TEMPO or BHT, only a trace amount of 127 was detected based on gas chromatology (GC) analysis. Based on these experimental results and related reports [71], a plausible mechanism is proposed. First, the photocatalyst Na2-eosin Y is irradiated to the excited state PC* and then converted to PC-by single-electron transfer, and PC-is oxidized by oxygen (from H2O2 and air) to provide the state photocatalyst and O 2-· . At the same time, phenylhydrazine 120 is oxidized to generate the radical cation 12 and the radical cation 128 is deprotonated to provide radical 129. The radical 129 line is then deprotonated to convert the intermediate 131.

Visible-Light-Enabled Seleno-and Sulfur-Bifunctionalization of Alkenes/Alkynes
Alkenes/alkynes are simple and abundant bulk commodities, and the vicinal difunctionalization of these feedstocks is of great importance in rapidly increasing molecular complexity with a variety of functional groups.
In 2013, Ogawa et al. [72] used a diselenide-Ph2P(O)H hybridization system to achieve highly regioselective hydroselenation of deactivated terminal alkynes under visible-light irradiation to give vinyl selenide 135. Based on free radical validation experi-Scheme 26. Sulfurization of aryl hydrazines.
When the sulfidation reaction was carried out with TEMPO or BHT, only a trace amount of 127 was detected based on gas chromatology (GC) analysis. Based on these experimental results and related reports [71], a plausible mechanism is proposed. First, the photocatalyst Na 2 -eosin Y is irradiated to the excited state PC* and then converted to PCby single-electron transfer, and PC-is oxidized by oxygen (from H 2 O 2 and air) to provide the state photocatalyst and O 2-· . At the same time, phenylhydrazine 120 is oxidized to generate the radical cation 12 and the radical cation 128 is deprotonated to provide radical 129. The radical 129 line is then deprotonated to convert the intermediate 131. Subsequently, nitrogen is eliminated from 131 to form the phenyl radical 132. On the other hand, the benzene sulfide radical 126a is generated by homolytic cleavage of 126 under visible-light irradiation. Finally, the target product, diphenyl sulfide 127a, is obtained by the radical coupling of 132 and 126b.

Visible-Light-Enabled Seleno-and Sulfur-Bifunctionalization of Alkenes/Alkynes
Alkenes/alkynes are simple and abundant bulk commodities, and the vicinal difunctionalization of these feedstocks is of great importance in rapidly increasing molecular complexity with a variety of functional groups.
In 2013, Ogawa et al. [72] used a diselenide-Ph 2 P(O)H hybridization system to achieve highly regioselective hydroselenation of deactivated terminal alkynes under visible-light irradiation to give vinyl selenide 135. Based on free radical validation experiments, a reasonable mechanism was proposed, as shown in Scheme 27. First, visible-light irradiation triggers the cleavage of the Se−Se single bond in the diselenides, generating the corresponding selenyl radicals. Next, the attack of the selenyl radicals on the terminal carbon of the olefin leads to the production of the vinyl intermediate. The vinyl radicals are captured by selenol to produce hydroselenate products, while the selenium radicals are regenerated. In addition, Ph 2 P(O)SeR generated as a by-product does not undergo addition reactions with the alkynes. This is in contrast to the addition reaction between the unoxidized Ph 2 PSePh and the alkynes. In 2019, Chen et al. [73] reported a multi-component cascade reaction of diselenides, alkynes, and sulfur dioxide in the presence of visible light. A novel β-sulfonylvinylsilane was prepared by this cascade reaction (Scheme 28). In addition, the conversion reactions of β-sulfonylvinylsilanes to 1,4-oxopyrimidine-4,4-dioxides and sulfonylacetylene derivatives were also investigated. The reaction was carried out in a 1,4-diazabicyclo(2,2,2)octane (DABCO)-(SO 2 ) 2 solution with CH 3 CN as the solvent and irradiated under blue light for 6 h. The substituents with halogen, methyl, methoxy, nitro, methoxycarbonyl, and amino groups were detected, respectively. The alkynes and diselenides of alkynes and diselenides showed experimentally that all reactions proceeded smoothly, but the conditions were not applicable to alkylalkynes. The formation of the product was significantly inhibited by the addition of the radical scavenger TEMPO under standard conditions, demonstrating that the transformation involved a radical pathway. Difunctionalization of alkenes enables rapid construction of complex molecules with broad applications in organic synthesis. In 2020, Yuan's group [77] reported a mild and effective strategy for the synthesis of acyloxy selenides via visible-light-induced bifunctionalization of styrene with diaryl diselenides and carboxylic acid dibasic compounds (Scheme 29). The work was carried out under white LEDs (20 W) with 4-methylstyrenes 141, diphenyl diselenides, and acetic acids 142 as substrates, CH3CN as a solvent, and 1.0 mol% RB as the required catalyst. The reaction was carried out for 14 h at room temperature to give the target product 143 with a 58% yield.
Controlled experimental studies confirmed that this process was carried out through a radical chain propagation process. On the basis of controlled and competitive experiments, a reasonable mechanism was depicted, as shown in Scheme 29 [78]. Initially, the rose bengal (RB) produces an excited state under the irradiation of blue LED light. Subsequently, the excited state RB* acquires electrons from diphenyl diselenide, providing RB •− and phenylselenide 19, which reacts with 4-methylstyrenes 141 to form 144, and another phenylselenide reacts with acetic acid 142 to form 145 and PhSeH, which is then oxidized by oxygen to PhSeSePh. Finally, the two radicals 144 and 145 react to give the target product 143. According to previous literature reports [74,75], a feasible reaction mechanism is proposed in Scheme 28. First, under blue light, the diselenide is excited to form selenium radicals. The addition of 136 gives the vinyl radical intermediate 138, which is then trapped by sulfur dioxide. A sulfonyl radical intermediate 139 is then formed. Subsequent attack on 136 produces the vinyl intermediate 140, which is captured by disulfide. Finally, product 137 is generated and provides recovery of the selenium radical [76].
Difunctionalization of alkenes enables rapid construction of complex molecules with broad applications in organic synthesis. In 2020, Yuan's group [77] reported a mild and effective strategy for the synthesis of acyloxy selenides via visible-light-induced bifunctionalization of styrene with diaryl diselenides and carboxylic acid dibasic compounds (Scheme 29). The work was carried out under white LEDs (20 W) with 4-methylstyrenes 141, diphenyl diselenides, and acetic acids 142 as substrates, CH 3 CN as a solvent, and 1.0 mol% β-Oxysulfides are a familiar organic molecule, widely used in organic synthesis precursors and functional compounds [79,80]. This unit is also present in biologically active pharmaceuticals and natural compounds [81]. However, there is no literature on the preparation of β-alkoxysulfides using diols as substrates. In 2019, Wang et al. reported a photochemical method for the preparation of bifunctional β-oxysulfides without photocatalysts and oxidants (Scheme 30). In this paper, styrene 146 and diphenyl disulfide 47 were used as model substrates to start the study. The desired products, 1-phenyl-2-(phenylthio)ethane-1-ol 147, were obtained in the presence of dichloromethane (CH2Cl2), water, CBr4, and blue LEDs in the system [82]. Subsequently, the prevalence of the reaction substrates, olefins, and thioethers was explored, and it was found that most of the expected products could be obtained. However, when aliphatic olefins or aliphatic disulfides were used as substrates, none of the expected products were observed.
To elaborate on the possible reaction mechanism, the authors performed a controlled experiment where the difunctionalization was almost suppressed when TEMPO was added to the reaction, which indicates that free radical processes are involved in the reaction. A potential mechanism is outlined in Scheme 30. First, under the irradiation of blue light, the disulfide 126a is homogenized to generate the sulfur radical 126b, and then 126b reacts with CBr4 to obtain the tribromomethyl radical, before the hydrogen is extracted from H2O or HOCH2CH2OH to obtain the corresponding hydroxyl group free radicals ( • OH) or alkoxy groups ( • OCH2CH2OH Controlled experimental studies confirmed that this process was carried out through a radical chain propagation process. On the basis of controlled and competitive experiments, a reasonable mechanism was depicted, as shown in Scheme 29 [78]. Initially, the rose bengal (RB) produces an excited state under the irradiation of blue LED light. Subsequently, the excited state RB* acquires electrons from diphenyl diselenide, providing RB •− and phenylselenide 19, which reacts with 4-methylstyrenes 141 to form 144, and another phenylselenide reacts with acetic acid 142 to form 145 and PhSeH, which is then oxidized by oxygen to PhSeSePh. Finally, the two radicals 144 and 145 react to give the target product 143.
β-Oxysulfides are a familiar organic molecule, widely used in organic synthesis precursors and functional compounds [79,80]. This unit is also present in biologically active pharmaceuticals and natural compounds [81]. However, there is no literature on the preparation of β-alkoxysulfides using diols as substrates. In 2019, Wang et al. reported a photochemical method for the preparation of bifunctional β-oxysulfides without photocatalysts and oxidants (Scheme 30). In this paper, styrene 146 and diphenyl disulfide 47 were used as model substrates to start the study. The desired products, 1-phenyl-2-(phenylthio)ethane-1-ol 147, were obtained in the presence of dichloromethane (CH 2 Cl 2 ), water, CBr 4 , and blue LEDs in the system [82]. Subsequently, the prevalence of the reaction substrates, olefins, and thioethers was explored, and it was found that most of the expected products could be obtained. However, when aliphatic olefins or aliphatic disulfides were used as substrates, none of the expected products were observed.

Construction of the C(sp)-S Bond
The carbon-heteroatom bond formation is used as a bridge for linking organic molecules to access complicated compounds with biological and pharmaceutical activity [83]. Although many synthetic strategies have been established for the C(sp 3 )-S and C(sp 2 )-S bond-forming formation, there are still important challenges for the construction of C(sp)-S bonds, particularly for the achievement of C(sp)-S bond formation [84]. In 2021, Wang et al. reported a strategy for the preparation of alkynyl sulfides using visible-light irradiation (Scheme 31) [85]. First, 2,2′-diaminodiphenyl disulfides 149 and phenylethynyl bromides 150 were chosen as model substrates, irradiated under blue light, and stirred in CH2Cl2 under an N2 atmosphere for 12 h to obtain the desired coupling products 151. The functional group tolerance of this visible-light-promoted C(sp)−S cross-coupling was investigated under optimized reaction conditions using various brominated alkynes and found to behave well for various brominated alkynes with different aromatic rings and good functional group compatibility.
To clearly illustrate the reaction and establish that the coupling reaction is initiated by disulfide 149 or bromoalkynes 150, control experiments were performed. The coupling reaction is stopped when the radical scavenger TEMPO is added to the reaction system; this significant inhibition means that the reaction may involve a free radical process. Based on the results of controlled experiments and the relevant literature, the transformation mechanism was proposed in Scheme 31. First, the intermediate product o-NH2C6H4S-(152) was produced by visible-light-induced homolysis of 2,2'-diaminodiphenyl disulfide (149). Then, 152 was added to brominated alkynes 150 to form an intermediate product 153, which was converted to product 151a by an elimination reaction. To elaborate on the possible reaction mechanism, the authors performed a controlled experiment where the difunctionalization was almost suppressed when TEMPO was added to the reaction, which indicates that free radical processes are involved in the reaction. A potential mechanism is outlined in Scheme 30. First, under the irradiation of blue light, the disulfide 126a is homogenized to generate the sulfur radical 126b, and then 126b reacts with CBr 4 to obtain the tribromomethyl radical, before the hydrogen is extracted from H 2 O or HOCH 2 CH 2 OH to obtain the corresponding hydroxyl group free radicals ( • OH) or alkoxy groups ( • OCH 2 CH 2 OH). An addition reaction of 126b with styrene 146 yields the intermediate 148. Finally, intermediate 148 with • OH or • OCH 2 CH 2 OH yields the desired products 147aa or 147ab.

Construction of the C(sp)-S Bond
The carbon-heteroatom bond formation is used as a bridge for linking organic molecules to access complicated compounds with biological and pharmaceutical activity [83]. Although many synthetic strategies have been established for the C(sp 3 )-S and C(sp 2 )-S bond-forming formation, there are still important challenges for the construction of C(sp)-S bonds, particularly for the achievement of C(sp)-S bond formation [84]. In 2021, Wang et al. reported a strategy for the preparation of alkynyl sulfides using visible-light irradiation (Scheme 31) [85]. First, 2,2 -diaminodiphenyl disulfides 149 and phenylethynyl bromides 150 were chosen as model substrates, irradiated under blue light, and stirred in CH 2 Cl 2 under an N 2 atmosphere for 12 h to obtain the desired coupling products 151. The functional group tolerance of this visible-light-promoted C(sp)−S cross-coupling was investigated under optimized reaction conditions using various brominated alkynes and found to behave well for various brominated alkynes with different aromatic rings and good functional group compatibility.

Conclusions
In this review, the recent progress in the synthesis and application of disulfide and diselenide as radical reagents with photochemical technology is reviewed, and the reaction scopes, limitations, and mechanisms of some of these reactions are also discussed. From the above discussion, it can be seen that the visible-light-promoted disulfide and diselenide radical reactions provide a stable and robust platform for the efficient construction of various selenium-/sulfur-containing heterocyclic compounds or bifunctional products. The successful examples described in this review convincingly demonstrate the high potential of disulfide and diselenide for drug discovery and applications. Among these synthesis methods, photochemistry and synergistic metal/photoredox catalysis techniques provide a more friendly and sustainable alternative for the application of disulfide and diselenide and illustrate the development prospects of thioether as free radicals.
Although significant progress has been made in this field over the last few decades, several issues and challenges remain in fully developing the potential applications of disulfide and diselenide, which should be further exploited and improved. More catalytic means should be explored in the application of disulfide and diselenide as free radical reagents, especially in terms of electrochemical synthesis methods, because electrochemical strategies have become increasingly powerful tools for the synthesis of organic compounds in recent years. Furthermore, the migration cyclization strategies involving disulfide and diselenide as radical reagents should be established to construct more complex polycyclic compounds, since polycyclic frameworks play an important role in medicinal chemistry and organic materials. In addition, the harmful consequences of metal catalysts and peroxides used in the reaction process cannot be ignored. It is our hope that this paper will encourage more researchers to contribute to this emerging field by developing more environmentally friendly catalytic systems. To clearly illustrate the reaction and establish that the coupling reaction is initiated by disulfide 149 or bromoalkynes 150, control experiments were performed. The coupling reaction is stopped when the radical scavenger TEMPO is added to the reaction system; this significant inhibition means that the reaction may involve a free radical process. Based on the results of controlled experiments and the relevant literature, the transformation mechanism was proposed in Scheme 31. First, the intermediate product o-NH 2 C 6 H 4 S-(152) was produced by visible-light-induced homolysis of 2,2'-diaminodiphenyl disulfide (149). Then, 152 was added to brominated alkynes 150 to form an intermediate product 153, which was converted to product 151a by an elimination reaction.

Conclusions
In this review, the recent progress in the synthesis and application of disulfide and diselenide as radical reagents with photochemical technology is reviewed, and the reaction scopes, limitations, and mechanisms of some of these reactions are also discussed. From the above discussion, it can be seen that the visible-light-promoted disulfide and diselenide radical reactions provide a stable and robust platform for the efficient construction of various selenium-/sulfur-containing heterocyclic compounds or bifunctional products. The successful examples described in this review convincingly demonstrate the high potential of disulfide and diselenide for drug discovery and applications. Among these synthesis methods, photochemistry and synergistic metal/photoredox catalysis techniques provide a more friendly and sustainable alternative for the application of disulfide and diselenide and illustrate the development prospects of thioether as free radicals.
Although significant progress has been made in this field over the last few decades, several issues and challenges remain in fully developing the potential applications of disulfide and diselenide, which should be further exploited and improved. More catalytic means should be explored in the application of disulfide and diselenide as free radical reagents, especially in terms of electrochemical synthesis methods, because electrochemical strategies have become increasingly powerful tools for the synthesis of organic compounds in recent years. Furthermore, the migration cyclization strategies involving disulfide and diselenide as radical reagents should be established to construct more complex polycyclic compounds, since polycyclic frameworks play an important role in medicinal chemistry and organic materials. In addition, the harmful consequences of metal catalysts and peroxides used in the reaction process cannot be ignored. It is our hope that this paper will encourage more researchers to contribute to this emerging field by developing more environmentally friendly catalytic systems.
Author Contributions: Writing-original draft preparation, C.W., Y.Z., T.Y. and F.L.; writing-review and editing, K.S., X.W.; funding acquisition, K.S. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the Qingchuang Technology Support Program of University in Shandong Province (2021KJ066).

Data Availability Statement:
The data presented in this study are available upon request from the authors.

Conflicts of Interest:
The authors declare no conflict of interest.